Reductive alkylation tertiary amine formation

Thus, two major differences between the reductive alkylation of primary and secondary amines are the increased steric hindrance in the latter case, and the fact that tertiary amine formation cannot proceed through a ketimine intermediate. 

Reductive alkylation of amines proceeds by the hydrogenation of the imine or enamine formed, in situ, by the condensation of the amine with a carbonyl compound. This reaction can give a mixture of products if the amine produced initially competes with the reactant amine in the carbonyl condensation step. The proper selection of reagent concentrations avoids this difficulty and leads to the formation of good yields of the desired product. 50 jhe use of a large excess of ammonia gives the primary amine as the predominant product (Eqn. 19.50). 51 An excess of a primary amine as the reactant leads to the preferential formation of the secondary amine product. An excess of the carbonyl compound gives the symmetrical secondary or tertiary amines (Eqn. 19.51). 50... 

Formic acid can also act as a donor of hydrogen. The driving force in this case is the formation of carbon dioxide. A useful application is the Clark-Eschweiler reductive alkylation of amines. Heating a primary or secondary amine with formaldehyde and formic acid results in complete methylation to the tertiary amine. ... 

Primary and secondary amines are usually converted to tertiary amines using formaldehyde and hydrogen in the presence of a catalyst (eqs. 5 and 6). This process, known as reductive alkylation (222), is attractive commercially. The desired amines are produced in high yields and without significant by-product formation. Quatemization by reaction of an appropriate alkylating reagent then follows. 

The reduction is usually effected catalytically in ethanol solution using hydrogen under pressure in the presence of Raney nickel. As in the reduction of nitriles (Section 5.16.1, p. 771), which also involves the intermediate imine, ammonia or the amines should be present in considerable excess to minimise the occurrence of undesirable side reactions leading to the formation of secondary and tertiary amines. These arise from the further reaction of the carbonyl compound with the initially formed amine product. Selected experimental conditions for these reductive alkylation procedures have been well reviewed.210 Sodium borohydride has also been used as an in situ reducing agent and is particularly effective with mixtures of primary amines and aliphatic aldehydes and ketones.211... 

Even if the imine may not be isolated, the transient species may sometimes be trapped by reaction with a suitable nucleophile. This is the basis of the reductive amination reaction in which an amine is formed from the reaction of ammonia with a carbonyl compound in the presence of a reducing agent such as sodium borohydride or formate. Use of a primary or secondary amine results in the specific formation of secondary or tertiary amines respectively (Fig. 5-45). This synthetic method allows the preparation of high yields of amines, in contrast to the unselective and uncontrollable reaction of alkylating agents with amines. A specific example involving the preparation of a-phenylethylamine from acetophenone is presented in Fig. 5-46. 

Aliphatic and aromatic amines react with nitrous acid to form N-nitroso derivatives. For example, dimethylamine hydrochloride on treatment with sodium nitrite and hydrochloric acid is converted to nitrosodimethyl amine in 90% yield. In like manner, N-nitrosomethylaniline is synthesized from N-methylaniline in 93% yield. The ready formation of these derivatives and the easy reconversion to the amine by reduction affords an advantageous procedure for separating secondary amines from primary and tertiary amines, as shown in the synthesis of N-ethyl-m-toluidine and other N-alkyl derivatives by the alkylation of w-toluidine. ... 

The extent to which secondary and tertiary amines are formed by reductive alkylation is controlled to some degree by the steric bulk of the amine and the carbonyl compound. The more hindered the system, the higher the temperature and hydrogen pressure needed to affect the reaction. While the reductive alkylation of secondary aliphatic amines with formaldehyde takes place under mild conditions (Eqn.l9.52X N,N-dimethylaniline was prepared by reductive alkylation over palladium at 120°C and 15 atmospheres pressure (Eqn. 19.53). 153 54 Reductive alkylation of aniline with acetone over palladium gave a 67% yield of the monoalkylaniline at 100°C and 40 atmospheres pressure but secondary amine formation using the more sterically accessible ketones, 2-tetralone or 2-indanone, took place at room temperature and 4 atmospheres pressure (Eqn. 19.54). 55 Palladium was the preferred catalyst in these reactions since with platinum or rhodium ring hydrogenation was also observed. 54,155... 

Tertiary amines. Using a secondary amine to decompose an ozonide derived from 1-alkene effects its alkylation. The amine initiates an eliminative fragmentation of the ozonide to generate an aldehyde and dialkylammonium formate. Schiff base formation from the aldehyde and another molecule of the amine is then followed by reduction by the formate ion. 

The azide synthesis is a better method for preparing primary amines than alkylation of ammonia because it avoids the formation of secondary and tertiary amines. This method involves treating an alkyl halide with sodium azide followed by reduction (Mechanism 23.1). 

Epoxides are another viable electrophilic partner for alkyl azides. Baskaran and coworkers found that azido-tethered epoxides afforded bicyclic, tertiary amines bearing a hydroxymethyl substituent upon treatment with a Lewis acid followed by reduction. This one-pot procedure was applicable to bicyclic azido epoxides with varying ring sizes, affording the corresponding bicyclic amines in preparatively useful yields (Table 7.8). These reactions probably involve the initial Lewis acid-assisted formation of a cation followed by azide attack. Migration and concomitant loss of N2 then generates an iminium ion, which persists until stereoselective reduction by hydride (Schane 7.32). 

The reaction of formic acid or a variety of formic acid derivatives, such as formate salts and formamides, with ammonia or a variety of amines, as well as various amine derivatives and salts such as ammonium formate salts, and carbonyl compounds, results in the reductive alkylation of the amine in which the entering alkyl group is derived from the carbonyl compound. This reaction is known as the Leuckart reaction [30]. By proper selection of reagents, primary, secondary, and tertiary amines may be prepared. In general this reaction is carried out at elevated temperatures without further solvents. More recent work indicates that magnesium chloride and ammonium sulfate are particularly useful catalysts in the preparation of tertiary amines by the Leuckart reaction [31]. 

In contrast to alkylations using [ C]MeI, quartemization cannot occur in reductive [ C]methylations. In reductive [ C]methylations of primary amines the use of a sufficiently large excess of amine can suppress formation of tertiary amine products. 

---